Scientific breakthrough on brutal brain disease

New insights into Multiple System Atrophy (MSA) have been revealed through groundbreaking research led by Dr Birger Victor Dieriks from the University of Auckland Centre for Brain Research.

MSA is so aggressive that within a few years, the neurodegenrative disorder can reduce vibrant, active individuals to a state of near-total immobility, reliant on full-time care, says Dieriks.

But hope could be on the horizon, thanks to a new study led by Dieriks, in collaboration with University of Sydney neuroscientist Professor Glenda Halliday.

Their research published this month in the prestigious journal, Brain, presents a paradigm-shifting discovery.

For decades, scientists believed that the primary culprits behind MSA's devastating effects were oligodendrocytes, the cells that produce a protective sheath around nerve fibres. In MSA patients these cells were known to accumulate clumps of a protein called α-synuclein.

Dieriks and his team have now uncovered that the real driver of MSA's aggressive neurodegeneration lies within the neurons themselves.

Using cutting-edge super-resolution microscopy and advanced α-synuclein antibodies, the researchers discovered that toxic protein clumps penetrate the nuclei of neurons in MSA patients. Once inside, they disrupt the 3D organisation of the nucleus, leading to its destruction and, ultimately, the death of the neuron.

“For years, the focus has been on the oligodendrocytes, because that’s where most of the α-synuclein clumps were found. But our research shows the real killer is the impact of α-synuclein aggregates on neurons – and this explains why MSA progresses so much faster than similar diseases, such as Parkinson’s,” says Dieriks.

MSA is often misdiagnosed as Parkinson’s disease, due to overlapping symptoms, such as muscle rigidity, balance issues, and tremors. However, MSA progresses at a much more alarming rate.

While Parkinson’s patients can live for decades, MSA patients typically survive only four to 10 years after the onset of symptoms. The rapid decline often leaves patients bedridden, with many losing the ability to speak or move.

Unlike Parkinson’s, where the loss of dopamine-producing neurons is the primary cause of symptoms, MSA is characterised by widespread failure in multiple brain systems, including those that control movement, balance, and functions like blood pressure and digestion. Until now, the reasons behind this extensive neuronal loss were poorly understood.

The study uncovered two distinct types of α-synuclein aggregates in MSA, with the aggregates in neurons being more resistant to breakdown and significantly more toxic than those in oligodendrocytes

“The α-synuclein aggregates in neurons are like a double-edged sword,” says study co-author Dr James Wiseman, who performed the lab work at the University of Auckland.

“They resist the body’s attempts to clear them out, while invading the very control centre of the neuron – the nucleus – causing catastrophic damage.”

This invasion leads to the destruction of the nuclear envelope, a protective barrier needed to maintain the integrity of the neuron’s genetic material. Once this barrier is compromised, the neuron’s ability to function and survive is irreversibly damaged.

The researchers observed significant damage to the nuclear structures of neurons in MSA patients.

These findings are more than just a scientific breakthrough – they represent a potential turning point in the fight against MSA.

By identifying neurons as the primary victims of α-synuclein toxicity, researchers can now focus on developing treatments that specifically target aggregates in neurons.

This could pave the way for new therapies to protect neurons from α-synuclein invasion or to enhance the cell’s ability to clear these toxic proteins, before they cause irreversible damage.

This research is remarkable because it comes from the only group in New Zealand dedicated to studying this horrendous disease, says Dieriks.

“We have carved out a niche in the global scientific community, pushing the boundaries of what we know about this disease, despite limited resources,” he says.

While more work is needed, this research takes a step towards unravelling the mysteries of MSA and offers a glimmer of hope for patients and their families.

Understanding the true drivers of neurodegeneration in MSA is the first step towards improving diagnosis and developing targeted therapies that could slow, or even halt, the disease’s progression.

“With each new discovery, the hope grows that one day, MSA will no longer be a life sentence but a condition that can be managed – or even cured,” says Dieriks.